研究领域
Chemical Biology/Biochemistry/Bioanalytical Chemistry
Professor Gelb's research is in the area of medicinal enzymology. All of the enzyme systems under study are medicinally important. The lab is comprised of researchers with a wide range of expertise. Thus, students will gain experience in or be exposed to a number of techniques including synthetic organic chemistry for the preparation of enzyme inhibitors and proteomic reagents, purification of enzymes using conventional and novel approaches, protein chemistry techniques for determining protein modifications, recombinant DNA approaches for the over-expression of enzymes and enzyme alteration by site-directed mutagenesis, and animal cell culture for the analysis of enzymatic processes in living cells. The Gelb group works in three areas: 1) phospholipases A2 and inflammation; 2) development of anti-parasite drugs; and 3) new methods for screening of genetic diseases and for quantification of proteins in complex mixtures.
Phospholipases A2 catalyze the breakdown of phospholipids in cell membranes. There is currently a lot of interest in this class of enzymes because they release arachidonic acid for the biosynthesis of eicosanoids and are thus important in promoting inflammation. There is medicinal interest in these enzymes both in universities and in pharmaceutical industries. The Gelb group, in collaboration with the laboratory of G. Lambeau (IPMC, Sophia Antipolis, France), has cloned a number of novel human and mouse secreted phospholipases A2. Structure, function, and regulation studies of these enzymes is currently an intense area of research in the Gelb group. The work involves structure-based design and synthesis of phospholipase A2 inhibitors, studies on the role of these enzymes in eicosanoid biosynthesis in mammalian cells, and the use of knockout mice to study the role of these enzymes in inflammatory diseases such as asthma and arthritis.
The Gelb group also works on the use of mass spectrometry for quantitative analysis of proteins, enzymes, and lipids. One major area is the development of newborn screening of enzyme deficiency diseases. Mass spectrometry offers a general way to assay enzymes, and it allows multiplexing for the analysis of several enzymes at the same time. Methods to analyze a set of treatable genetic diseases called lysosomal storage diseases have advanced from the Gelb group to newborn screening centers worldwide. This project offers an interesting mix of synthetic organic chemistry and bioanalytical chemistry. A second area is the development of tagging reagents for quantitative analysis of proteins and lipids and methods for making detection by mass spectrometry more sensitive.
The third area of research in the Gelb group is medicinal chemistry of anti-parasitic agents. We are part of a UW-centered team to develop new drugs for African sleeping sickness, Malaria, and Chagas disease.
A final area is in collaboration with Professor Dustin Maly and involves the use of a genetically encoded switch that can be triggered by a small MW compound. This switch has widespread potential use for example in gating proteins to different regions of the cell and in disrupting protein-protein interactions. This is a very exciting new area of chemical biology
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Duffey, T. A., Sadilek, M., Scott, C. R., Turecek, F., Gelb, M. H. (2010) "Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: Application to screening newborns for Mucopolysaccharidosis IV (Maroteaux-Lamy Syndrome)", Anal. Chem., 82:9587-9591.
Kraus, J.M., Verlinde, C.L.M.J., Karimi, Mandana, Lepesheva, G.I., Gelb, M.H., and Buckner, F.S. (2009) "Rational modification of a candidate cancer drug for use against chagas disease." J. Med Chem. 52:1639-1647.
Bendale, P, Olepu, S, Suryadevara, PK, Bulbule, V, Rivas, K, Nallan, L, Smart, B, Yokoyama, K, Ankala, S, Pendyala, PR, Floyd, D, Lombardo, LJ, Williams, DK, Buckner, FS, Chakrabarti, D, Verlinde, CL, Van Voorhis, WC, Gelb, MH (2007) "Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials," J. Med. Chem., 50, 4585-4605.
Gelb, M.H., Brunsveld, L., Hrycyna, C.A., Michaelis, S., Tamanoi, F. , Van Voorhis, W.C. and Waldmann, H. (2006) "Therapeutic intervention based on protein prenylation and associated modifications," Nature Chem. Biol. 10, 518-528
B.B. Rubin, G.P. Downey, A. Koh, N. Degousee, F. Ghomashchi, L. Nallan, E. Stefanski, B.P. Smart, T.F. Lindsay, V. Cherepanov, E. Vachon, D. Kelvin, M. Sadilek, G.E. Brown, M.B. Yaffe, J. Plumb, S. Grinstein, M. Glogauer, and M.H. Gelb, "Cytosolic phospholipase A2 alpha is necessary for platelet activating factor biosynthesis, efficient neutrophil mediated bacterial killing and the innate immune response to pulmonary infection," J. Biol. Chem. 2004 280, 7519.
C.M. Mounier, F. Ghomashchi, M.R. Lindsay, S. James, A.G. Singer, R.G. Parton, and M.H. Gelb, "Arachidonic acid release from mammalian cells transfected with human groups IIA and X secreted phospholipase A2 occurs predominantly during the secretory process and with the involvement of cytosolic phospholipase A2-a," J. Biol. Chem. 2004 279 25024.
N.M. Okeley and M.H. Gelb, "Membrane Transport, Structure, Function, and Biogenesis: A designed probe for acidic phospholipids reveals the enriched anionic character of the cytosolic face of the mammalian plasma membrane," J. Biol. Chem. 2004, 279 21833. A.G. Singer, F. Ghomashchi, C. Le Calvez, J. Bollinger, S. Bezzine , M. Rouault, M. Sadilek, M. Lazdunski, G. Lambeau and M.H. Gelb, "Interfacial Kinetic and Binding Properties of the Complete set of Human and Mouse Groups I, II, V, X, and XII Secreted Phospholipases A2," J. Biol. Chem. 2002 277 48535.
S.H. Yang, M.O. Bergo, J.I. Toth, X. Qiao, Y. Hu, S. Sandoval, M. Meta, P. Bendale, M.H. Gelb, S.G. Young, L.G. Fong, "Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Bilford progeria syndrome mutation," Proc. Natl. Acad. Sci2005 102 10291.
O. Hucke, M.H.Gelb, C.L. Verlinde and F.S. Buckner, "The protein farnesyltransferase inhibitor tipifarnib as a new lead for the development of drugs against Chagas disease," J. Med. Chem. 2005 48 5415.
L. Nallan, K.D. Bauer, P. Bendale, K. Rivas , K. Yokoyama, C.P. Horney, P.R. Pendyala, D. Floyd, L.J. Lombardo, D.K. Williams, A. Hamilton, S. Sebti, W.T. Windsor, P.C. Weber , F.S. Buckner , D. Chakrabarti, M.H. Gelb, and W.C. Van Voorhis, "Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity," J. Med. Chem., 2005 48 3704.
Y. Li, C.R. Scott, N.A. Chamoles, A. Ghavami, B.M. Pinto, F. Turecek and M.H. Gelb, "Direct Multiplex Assay of Lysosomal Enzymes in Dried Blood Spots for Newborn Screening," Clin. Chem. 2004 50 1785.
Y. Lu, P. Bottari, F. Turecek, R. Aebersold, and M.H. Gelb, "Absolute Quantification of Specific Proteins in Complex Mixtures Using Visible Isotope-Coded Affinity Tags," Anal. Chem. 2004 76 4104.
Y. Li, K. Brockman, F. Turecek, C.R. Scott and M.H. Gelb, "Tandem Mass Spectrometry for the Direct Assay of Enzymes in Dried Blood Spots: Application to Newborn Screening for Krabbe Disease," Clin. Chem. 2004, 50: 638.
P. Bottari, R. Aebersold, F. Turecek and M.H. Gelb, "Design and Synthesis of Visible Isotope-Coded Affinity Tags for the Absolute Quantification of Specific Proteins in Complex Mixtures," Bioconj. Chem. 2004
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